6alpha, 21-difluoro-9alpha, 11beta-dichloro-16alpha, 17alpha-alkylidene-dioxypregn-4-ene-3, 20 diones



United States Patent Oi. ce 5 222;

can be employed for dermatological inflammatory condi- 3,409,613 tions, such as contact dermatitis, eczematous dermatitis,

611,21 DIFLUORO DICHLORO 6 pruritus ani, and the like, with a minimum if any sys- ALKYLIDENE DIOXYPREGN 4 ENE 3,20 temic derangement. These compounds may be adminisgg ig Palo Alto, Calif assign to syntex C 5 tered in the form of solutions, suspensions, creams, ointporation, Panama, Panama, a corporation of Panama E PY and the l y, VieW 0f thell N D i Fil J fl 23, 195 s 5 ,41 high activity, the compositions will contain up to about 3 Claim (C1, 260 239,55) 0.25% by weight of active steroid. As is customary, the

precise dosage may be varied depending upon the condition being treated and for some of these, such as main- ABSTRACT OF THE DISCLOSURE 10 tenance therapy of large areas or occlusive dressing Novel 6u, 1 difll10 -9 1} -di 0- 6 -al y therapy, compositions containing about 0.01% or less,

YP ,20-diones and the corresponding by Weight, are preferred. Various other therapeutic agents,

pregna-1,4-dienes having topical anti-inflammatory activa for exam le, antibiotics such as neomycin, may of ity. course be included in suitable compositions.

The compounds of the present invention may be prepared chemically in a number of ways. Thus a 60L-flll0l'0- The present invention relates to novel cyclopentano- 16a,17walkylidenedioxypregna 49(11) dien polyhydrophenanthrene derivatives and to processes for dione 21 acetate or the Corresponding 1,4,9(11) trien lt/[ 512 g lically the present invention pertains to 20 l fii with g? g 21 chloroo t ie t orr com- 6a,21-difluoro-9a,11fi-dichloro-16ix,17u alkylidenedloxy- 3% basiec 1,5332; 2% fi fi if P g- 3 and to PQ Q Pregna' the 9a,1lfl-dichloro-Zl-hydroxy intermediate is converted The confpounds of thls mventlon repre' to an alkyl or aryl sulfonate such as the mesylate or sented by the followmg structur a1 formula: 25 tosylate which when treated with potassium fluoride yields CH -r 2 dioxypregn-4-ene-3,20-dione, or in those cases in which c=o a -1,4-diene is employed as the starting material, the :1 3 6a,21-difluoro-9a,1lB-dichloro-l6a,17 alkylidenedioxy- .OCB pregna-1,4-diene-3,20-dione.

CH3 Alternatively a 60: fluoro l60t,l7oc alkylidenedioxypregna-4,9(l1)-dien-21-ol-3,20-dione or the corresponding -1,4,9(11)-triene is first converted to the 21-fluoro derivative, in the manner previously described, and the O 6a,2l-difluoro-4,9(ll)-diene or 6a,2l-diflu0ro-1,4,9(11)- triene is then chlorinated to yield the corresponding ,21- difluoro-9u,11fi-dichloro-16a,17a alkylidenedioxypregnwherein each of A and B is hydrogen or lower alkyl and 4-ene-3,20-dione, or in the case of the 1,4,9(1l)-triene Z is a carbon-carbon double bond or a carbon-carbon starting material, the 60:,21 -dlfiu01'0-9ot,11/3-diChlOrO- single bond between C-1 and C-2. The term lower alkyl 40 160,17a-alkylidenedioxypregna 1,4 diene 3,20-dione. includes methyl, ethyl, propyl, butyl and pentyl. These reactions may be represented as follows: oii oiz fHZOR c=o c=o c1 ......0 ,A B .o a Z Z 1) tosylation 2) KB 2) tosylatlon i ca -r l on l I 2- iana, A

,C 1 ...0 A ,C

o I F (IV) E The foregoing compounds possess an extremely high level of topical anti-inflammatory activity with a lower In the foregoing, A, B and Z are as previously defined level of systemic activity. Accordingly these compounds and R is either hydrogen or acyl, e.g. acetyl, R being H the sequence II lV I-and R-being aeyl in the'sequence Particularly preferred compounds of the present invention are those in which each of A and B is methyl. Moreover the compound wherein each of A and B is methyl and Z is a double bond is especially useful.

The following examples will serve to further typify the nature of this invention. These examples are presente however solely for the purpose of illustration and should not, therefore, be considered as a limitation on the scope of this invention.

EXAMPLE 1 (A) Nineteen grams of 6ot-fluoro-16a,17a-isopropylidenedioxy 2 l-acetoxypregna- 1,4,9 1 l -triene-3 ,20-dione are suspended in 152 ml. of methanol to which has been added 475 mg. of sodium in 38 ml. of methanol. This reaction mixture is stirred for 45 minutes at from 20 to 25 C. and then neutralized with acetic acid. After evaporation to dryness, the residue is dissolved in methylene chloride and this solution is washed with water, dried over sodium sulfate and concentrated. Addition of methanol to the concentrate followed by further concentration yields a slurry which is filtered. The solid thus collected is washed with cold methanol and dried to yield 6a-fluoro- 16u,17a isopropylidenedioxypregna l,4,9(11)-trien-2lol-3,20-dione, M.P. 245 C. (dec), [IX]D+Z4O.

A (B) To a cooled solution of 3.4 g. of 6a-fluoro-l6a,l7aisopropylidenedioxypregna 1,4,9(1l) trien-21-ol-3,20- dione in 20 ml. of 9:1 chloroformzpyridine is added in small portions 1.4 .g. of tosyl chloride. The reaction mixture is allowed to stand for 14 hours at C. and is then washed with dilute hydrochloric acid, water and sodium bicarbonate solution. The chloroform is removed by evaporation under reduced pressure and the residue is dissolved in acetone. This acetone solution is added to a refluxing suspension of 10 g. of potassium fluoride in 50 ml. of dimethylformamide. After refluxing for 5 hours, the mixture is cooled and poured into water. The solid which forms is collected by filtration, dried and recrystallized from acetone and hexane to yield 6a,21-difll10lO-16u,- 17a isopropylidenedioxypregna 1,4,9(11)-triene-3,20- dione, M.P. 267 C. (dec.), [a] +9.

(C) Five grams of 6a,21 difluoro-16a,17a-isopropylidenedioxypregna 1,4,9(l1) triene-3,20-dione are dissolved in 50 ml. of chloroform containing 5 ml. of pyridine. The mixture is held at 0 for 15 minutes while a stream of chlorine is bubbled through. The mixture is then poured into a 10% aqueous sulfuric acid solution and the organic layer separated. This layer is washed with 5% aqueous sodium bicarbonate and water to neutrality, dried over sodium sulfate and evaporated to dryness to yield 6a,2l difluoro-9a,llB dichloro-lfia,l7a-isopropylidenedioxypregna-l,4-diene-3,20-dione, M.P. 245 C. (dec.), [011 133.

In a similar fashion from 6u-fluoro-l6u-isopropylidenedioxy 21-acetoxypregna-4,9 (1 1 -diene-3,20- dione, there is obtained via the procedures of this example, 60,21 difluoro 9a,1IB-dichloro-l6a,l7u-isopropylidenedioxypregn-4-ene-3,20-dione.

EXAMPLE II EXAMPLE 111 By subjecting 6ot-lluoro-l6a,l7a-ethylidenedioxy2 l-aceheated at 90 C. for 20 toxypregna-l,4,9(l1) triene-3,20di0ne. to the procedure of Example I, there is obtained 6a,2l-difluoro-9u,l-119-dichloro 16a,l7u-ethylidenedioxypregna-l,4-diene-3,20-dione.

EXAMPLEIV Seventy five milligrams of 604,21 difluoro 9a,1.l[3-dlchloro 16a,17a-isopropylidenedioxypregna-1,4-diene-3,- 20-dione is dissolved with stirring at 80 C. in 39.38 g.= of propylene glycol. There is then added with stirring a filtered melt of 75 g. of stearic acid, 39 g. of Span 60, 7.5 g. of Span 80, 21 g. of Tween 60 and 375 mg. of propylparaben. There is next added a solution of 1.35 g. of methylparaben in 555 g. of sterile deionized water. The mixture is allowed to cool to a temperature of 25 to 30 while stirring is continued, solidification occurring at about C.'Ther is then slowly added with stirring, a solution of 75 mg. of anhydrous citric acid in 15.5 g. of sterile deionized water. The weight of this mixture is then adjusted to 750 :g. with sterile deionized water to produce a 0.01% cream suitable for maintenance therapy and occlusive dressing therapy of various dermatoses.

By employing 187.5 mg. of the steroid in the foregoing procedure, a 0.025% cream is obtained, suitable for ad: junctive therapy of acute or chronic dermatoses.

EXAMPLE v Twenty five milligrams of 60,2l difluoro 9a,1lB-di chloro 16u,l7oc isopropylidenedioxypregn-4-ene-3,20-dione, which has been milled on a ball mill to a particle size of under 10 microns, and 575 mg. of neomycin sulfate, similarly micronized, are added to 3.4g. of white petrolaturn, USP, which has been melted at a temperature of 50 to C. This mixture is thoroughly mixed and passed through an Eppenbach colloid mill. The mill is then rinsed with 96 g. of melted white petrolatum which is divided into four portions. These rinsings are combined with the principal mixture and the entire bulk is stirred until it has attained room temperature. The resulting 0.05% ointment is suitable for treatment of inflammatory dermatoses complicated by infection where an emollient effect or lubrication is desirable.

EXAMPLE VI Ninety five milliliters of propylene glycol, USP, are minutes and then cooled to C. In this liquid are dissolved with agitation 10 mg. of 6a,2l difluoro 9a,11p-dichloro-16u,17a-isopropylidenedioxypregn 1,4-diene 3,20-dione and 10 mg. of anhydrous citric acid, USP. The volume of the resulting solution is adjusted to a total of 100 ml. with additional propylene glycol and allowed to attain temperature. The resulting 0.01% solution may be employed for the treatment of inflammatory dermatoses in intertriginous or hairy sites.

What is claimed is: 1. A compound of the formula:

wherein each of A and B is hydrogen or lower alkyl and Z is a carbon-carbon double bond or a carbon-carbon single bond between C1 and C2.

2. 6a,21 difluoro 9a,llB-dichloro-16u,l7a-isopropylidenedioxypregn-4-ene-3,20-dione.

OTHER REFERENCES idenedioxypregna-1,4-diene-3,20-dione.

Heller, M. et aL, Steroids, May 1965, pp. 615-635. References Cited LEWIS GOTIS, Primary Examiner. UNITED STATES PATENTS 5 E. G. LOVE, Assistant Examiner. 3,053,838 9/1962 Fried 260239.55 

